The overarching goal of this program project is to advance the science of individualizing treatment to improve outcomes on the basis of response to therapy. Neoadjuvant chemotherapy (NAC) provides the opportunity to assess response to systemic therapy prior to surgery in women with high risk early breast cancer. The optimal outcome is the complete eradication of tumor, (pathologic complete response (pCR)), which is strongly associated with improved long-term survival and is a surrogate endpoint for accelerated drug approval. Conversely, women with significant residual cancer burden (RCB 2/3) suffer event free survival of less than 60% at 3-5 years. Redirecting therapy in poor responders could dramatically improve breast cancer survival in the highest risk women and minimize toxicities in early responders. The neoadjuvant I-SPY 2 adaptive clinical trial platform, designed to accelerate phase II development of new agents for stage II/III breast cancer is the ideal setting for this work. MRI will serve as a foundation for an integrated residual cancer burden assessment tool (?iRCB?), optimized by tumor subtype and pathway. Two decades of MRI imaging research in the I-SPY program have provided the necessary technology, bioinformatic and statistical approaches, and validation datasets to optimize the iRCB tool to serve as the trigger to redirect to rationally selected, biologically targeted agents. The advances from each project coalesce in Project 1, where we have developed the mechanics of integrating the pieces to determine whether treatment redirection on the basis of pathway abnormalities and avoiding the additional toxicity of chemotherapeutic agents in the setting of complete or poor response leads to better outcomes. Project 2 contributes the tools for the optimization of the iRCB, using advances in imaging methods (diffusion weighted imaging and breast PET) and a longitudinal model that includes molecular data from diagnosis, and an inter-regimen biopsy to confirm absence or presence of disease and accurately classify excellent and poor response (RCB 0 and RCB 2/3, respectively). Project 3 will provide an understanding of the dynamics of the biology of response and treatment resistance, and Project 4 will delineate the rational selection of `second chance? therapies based on the biology and knowledge of agents already or being developed. We will work closely with the FDA over the course of this Program Project to establish the subtype specific thresholds for iRCB. The final result will be an evolution of the existing I-SPY Trial (into ?I-SPY2+?) that employs an innovative Sequential Multiple Assignment Randomization Trial (SMART) design to maximize both clinical impact and knowledge generation, while closely reflecting the realities of current clinical practice. Taken together, these projects leverage an established, successful, efficient, and highly innovative clinical trial platform and an experienced, collaborative research team to address a critical clinical issue in breast cancer. The innovative approach employed will mark a milestone in the implementation of personalized medicine in breast cancer and generate an unprecedented view of the molecular evolution of treatment resistance.